ABSTRACT Chikungunya virus (CHIKV) causes a debilitating disease characterized by high fever, acute polyarthalgia and polyarthritis. While the symptoms can resolve in weeks, there are cases where the symptoms can reoccur for up to years. Another great concern is the recent global spread of the virus, having recently arrived in the Americas. The severity of the symptoms, rapid spread of the virus and the lack of available treatment options makes CHIKV a serious concern. Understanding mechanisms underlying the pathophysiology of disease would greatly aid identifying effective therapeutics. A clear way to address this problem is the establishment of viable infection models that mimics in vivo infections in humans coupled with an analysis of host factors specifically produced during infection. In particular to better understand joint and bone manifestations of chronic disease. Towards this goal, we have studied host factors recruited by the virus during infection in a 2D cell culture model. While this and similar studies are useful, a 3D infection model more closely mimics in vivo infection in humans and constitutes the subject of this application. In Aim #1 we will test the permissivity of osteoblast, osteoclast and endothelial cells to infection in a 2D co-culture model. Further, we will test CHIKV infection in tri-culture model. In Aim #2 we will develop a chronic CHIKV infected vascularized bone model. Further, we will isolate and analyze exosomal proteins in order to identify potential therapeutic targets. We hypothesize that viral infection in this system will more closely mimic human infection therefore; interrogating intercellular communication during infection will provide mechanistic detail about CHIKV induced bone pathology and offer targets for therapeutic intervention. Upon completion of these studies we will gain a deeper mechanistic understanding of chronic CHIKV-induced bone pathology and provide a first of its kind model system for studying CHIKV disease.